Tuesday, July 1, 2025 7/1/2025

Systems-to-structure approaches for defining mitochondrial protein function

Award Number: R35GM131795
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2019
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Systems-to-structure approaches for defining mitochondrial protein function - PROJECT SUMMARY Mitochondria are centers of metabolism and signaling, and their functions are essential for all but a few eukaryotic cell types. Despite the widespread importance of these organelles, many aspects of mitochondrial biology remain remarkably obscure. This fact contributes to our poor ability to diagnose mitochondrial diseases and our near complete inability to rectify mitochondrial dysfunction therapeutically. This dysfunction is associated with ~350 rare inborn errors of metabolism and an increasing number of common diseases—including Parkinson’s, Alzheimer’s, various cancers, and type 2 diabetes—often through distinct, yet unclear means. A major bottleneck to further understanding mitochondrial processes and addressing their dysfunction in human disease is that the proteins driving them have often not been identified. Concurrently, the basic biochemical functions of many mitochondrial proteins that may fulfill these roles are undefined, or at best are poorly understood. This reality was made manifest by my efforts to generate MitoCarta, which doubled the number of known mammalian mitochondrial proteins and revealed a striking ~300 lacking any annotated function. Thus, an overarching goal of my research program is to achieve a more comprehensive understanding of mitochondrial biology by systematically establishing the functions of orphan mitochondrial proteins and their roles within disease-related processes. We do so by first devising novel, multi-dimensional analyses designed to make new connections between these proteins and established pathways and processes. These include customized, multiomic analyses of yeast and human cell gene knockouts, deep mutational scanning approaches, large-scale genetic screens, and other mass spectrometry-based investigations. We then employ mechanistic and structural approaches to define the functions of select proteins at biochemical depth, and chemical biology approaches to design small molecules to manipulate their functions in vitro and in vivo. This strategy leads us into diverse and unanticipated new directions; however, we also maintain a persistent focus on the biochemistry, biosynthesis, and transport of coenzyme Q (CoQ). We are driven to define how this remarkable, redox-active, extremely hydrophobic molecule is produced in mitochondria, distributed throughout the cell, and how its cofactor and antioxidant functions empower an ever-growing list of diverse biochemical processes. Overall, these “systems biochemistry” efforts promise to help establish a deep, mechanistic understanding of mitochondrial biochemistry that will motivate novel therapeutic strategies for the vast array of human disorders rooted in mitochondrial dysfunction.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $348,121 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	003	8	4/18/2025	NON-COMPETING CONTINUATION	$464,161
2025	2024	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	001	7	1/20/2025	COMPETING CONTINUATION	-$116,040
2025	2024	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	000	7	11/4/2024	COMPETING CONTINUATION	$0
2025	2023	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	002	6	2/18/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $348,121

Issue Date FY: 2024 ( Subtotal = $670,205 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Biomedical Research and Research Training	001	7	4/12/2024	COMPETING CONTINUATION	$670,205
2024	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Biomedical Research and Research Training	000	6	4/11/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $670,205

Issue Date FY: 2023 ( Subtotal = $645,775 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	000	6	4/28/2023	NON-COMPETING CONTINUATION	$645,775
														Subtotal = $645,775

Issue Date FY: 2022 ( Subtotal = $645,775 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	000	5	3/14/2022	NON-COMPETING CONTINUATION	$581,197
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	001	5	6/22/2022	NON-COMPETING CONTINUATION	$64,578
														Subtotal = $645,775

Issue Date FY: 2021 ( Subtotal = $645,775 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	000	4	3/11/2021	NON-COMPETING CONTINUATION	$645,775
														Subtotal = $645,775

Issue Date FY: 2020 ( Subtotal = $645,402 )
2020	2020	MORGRIDGE INSTITUTE FOR RESEARCH, INC., THE	330 N ORCHARD ST	MADISON	WI	53715	DANE	USA	Biomedical Research and Research Training	001	2	5/11/2020	NON-COMPETING CONTINUATION	-$702,082
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	004	3	8/30/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$140,679
2020	2020	MORGRIDGE INSTITUTE FOR RESEARCH, INC., THE	330 N ORCHARD ST	MADISON	WI	53715	DANE	USA	Biomedical Research and Research Training	000	2	3/19/2020	NON-COMPETING CONTINUATION	$702,082
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	002	3	5/12/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$645,402
2020	2019	MORGRIDGE INSTITUTE FOR RESEARCH, INC., THE	330 N ORCHARD ST	MADISON	WI	53715	DANE	USA	Biomedical Research and Research Training	003	1	8/30/2020	NEW	-$140,679
														Subtotal = $645,402

Issue Date FY: 2019 ( Subtotal = $702,082 )
2019	2019	MORGRIDGE INSTITUTE FOR RESEARCH, INC., THE	330 N ORCHARD ST	MADISON	WI	53715	DANE	USA	Biomedical Research and Research Training	000	1	3/22/2019	NEW	$702,082
														Subtotal = $702,082

Grand Total All Awards = $4,303,135

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Systems-to-structure approaches for defining mitochondrial protein function

Award Number: R35GM131795

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2019

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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